Chemotherapy with atezolizumab for small cell or neuroendocrine carcinoma of the prostate: A single institution experience

Christopher E. Wee | Brian A. Costello | Jacob J. Orme |
J. Fernando Quevedo | Lance C. Pagliaro

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence
Lance C. Pagliaro, 200 1st Street SW, Rochester, MN 55905, USA.
Email: [email protected]

Abstract

Introduction: Chemotherapy in combination with immunotherapy has a proven survival benefit compared to chemotherapy alone in extensive stage small cell lung cancer (SCLC) and is the new standard of care. Since extrapulmonary small cell carcinomas (SCCs) are less common, treatment paradigms are reasonably extra- polated from SCLC regimens. We examined our institution’s experience utilizing the combination of chemotherapy and immunotherapy (as used in SCLC) for SCC and neuroendocrine carcinoma of the prostate.
Methods: Utilizing an institutional database search tool, we queried the electronic medical record to identify patients with SCC or neuroendocrine carcinoma of the prostate who had been treated with atezolizumab and chemotherapy. We recorded patient characteristics, including age, pathology, and disease extent. Treatment characteristics included number of prior treatments, use of concominant androgen deprivation, number of cycles of immunotherapy, and prior systemic therapies (in- cluding those for adenocarcinoma of the prostate). Progression free survival (PFS) and overall survival (OS) were the primary outcomes.
Results: We identified seven men who received atezolizumab for metastatic pros- tate cancer with a small cell or neuroendocrine component. In six of the seven patients, the combination of carboplatin, etoposide, and atezolizumab was the first‐ line of treatment after diagnosis of small cell or neuroendocrine carcinoma. Two of the seven patients had de novo small cell/neuroendocrine pathology, while the other five had transformation from a preexisting adenocarcinoma. In the patients who received chemotherapy plus immunotherapy in the first‐line setting, at a median follow‐up of 6.5 months (range: 1.5–15.1) the median PFS was 3.4 months and median OS was 8.4 months.
Conclusion: Small cell or neuroendocrine carcinoma of the prostate was associated with poor survival outcomes despite adding immunotherapy (atezolizumab) to chemotherapy (carboplatin and etoposide). To our knowledge, there has been no demonstrable benefit of adding immunotherapy to chemotherapy in this setting.

KEYWOR DS
atezolizumab, neuroendocrine, prostate cancer, small cell carcinoma

1 | INTRODUCTION

While the vast majority of small cell carcinomas occur in the lungs, there are also extrapulmonary small cell carcinomas, for which the prostate is one of the more frequent sites of origin.1,2 This includes both de novo small cell carcinoma of the prostate and small cell arising from, or in conjunction with, prostatic adenocarcinoma.
Given the rarity of prostatic small cell carcinoma, the data from prospective trials regarding treatment outcomes are limited. Clinical experience suggests that it should be treated similarly to small cell lung cancer (SCLC). Accordingly, the National Comprehensive Can- cer Network guidelines for small cell/neuroendocrine prostate cancer suggest platinum‐based chemotherapy (cisplatin/etoposide, carboplatin/etoposide, or docetaxel/carboplatin) and refer to the SCLC guidelines for other possible therapy options.3
For decades, a platinum drug plus etoposide was the standard treatment for SCLC.4 After years of minimal therapeutic break- throughs, Horn et al.5 reported in IMpower133 that the addition of atezolizumab to chemotherapy improved overall survival (OS) and progression‐free survival (PFS) compared to chemotherapy alone in extensive stage SCLC. This combination chemoimmunotherapy is now the standard of care for frontline therapy. The clinical benefit of adding a checkpoint inhibitor to the standard chemotherapy regimen in small cell/neuroendocrine carcinoma of the prostate remains un- clear. We aim to demonstrate our institution’s experience using chemoimmunotherapy in this setting.

2 | MATERIALS AND METHODS

After our institution’s IRB reviewed our application and deemed our retrospective review exempt, patients with small cell or neu- roendocrine carcinoma of the prostate who received a checkpoint inhibitor (such as atezolizumab, pembrolizumab, nivolumab, durva- lumab, or avelumab) were reviewed. To identify these patients, we utilized an institutional database query search tool, which scanned our electronic medical record for keywords. These searches included terms “small cell,” “neuroendocrine,” “atezolizumab,” “pembrolizumab,” “nivolumab,” “durvalumab,” “prostate cancer,” “carcinoma of prostate,” and “adenocarcinoma of prostate.” Although we had initially intended to include patients who received any of the above listed immune checkpoint inhibitors (ICIs), we ultimately narrowed the scope of our analysis to patients who received ate- zolizumab, since patients who received atezolizumab were treated with a more consistent chemotherapy backbone (platinum + etopo- side), similarly to patients with SCLC. In our experience, patients who were treated with other ICIs (n = 6) had significant heterogeneity in line of therapy and the administration of concominant agents; only two received an ICI in the first‐line setting, and three received ICI alone. Therefore, we only included patients who had recevied atezolizumab as the ICI.
Patient characteristics included age at time of immunotherapy initiation, pathology (small cell, neuroendocrine, or both), involved sites at start of immunotherapy, and whether the small cell or neu- roendocrine carcinoma presented de novo or transformed from ex- isting adenocarcinoma. Treatment characteristics obtained included number of prior treatments, use of concominant androgen depriva- tion, number of cycles of immunotherapy, and prior systemic thera- pies (including those for adenocarcinoma of the prostate). Progression free survival was calculated from time of initiation of chemoimmunotherapy to progression or death, while overall survival was calculated from time of initiation of chemoimmunotherapy to death. Duration of follow‐up was determined from date of initiation of chemoimmunotherapy until death or latest follow‐up through January, 2021. PFS and OS were calculated by Kaplan–Meier method using the statistical software R: A Language and Environ- mental for Statistical Computing (Vienna, Austria).6

3 | RESULTS

We identified seven men who had received atezolizumab for meta- static prostate cancer with a small cell or neuroendocrine component. In six of the seven patients, a combination of carboplatin, etoposide, and atezolizumab was the first‐line of treatment after diagnosis of small cell or neuroendocrine carcinoma. Patient #6 had been treated with first‐line carboplatin and etoposide only, leading to a complete response for 7 months until disease progression. The addition of atezolizumab to carboplatin and etoposide was used after disease relapse, and was the starting point for our calculations. Two of the seven patients had de novo small cell/neuroendocrine pa- thology, while the other five had transformation from a preexisting adenocarcinoma. Specific characteristics, including pathology, number of cycles of chemotherapy and immunotherapy, duration of follow‐up, PFS, and OS are in Tables 1 and 2. Table 1 contains only patients who have small cell histology AND received chemother- apy + atezolizumab in the first‐line setting. Table 2 includes two pa- tients with other neuroendocrine prostate tumors and patient #6 who received subsequent line chemoimmunotherapy.
Of the six patients who received chemotherapy + atezolizumab in the first‐line setting, with a median follow‐up of 6.5 months (range: 1.5–15.1) the median PFS and OS by Kaplan–Meier method was 3.4 months (95% confidence interval: 1.4, NA) and 8.4 months (2.9, NA), respectively. Three of the seven patients had died by time of data censoring, thus the median OS had not been reached. No patients had any significant immune‐related toxicities.

4 | DISCUSSION

Because of the demonstrated survival benefit of adding atezolizumab to frontline chemotherapy in SCLC (vs. chemotherapy alone), we had hypothesized that the addition of atezolizumab to chemotherapy may provide benefit in our cohort of prostatic small cell carcinoma
patients treated with this regimen. Our real‐world clinical experience
with carboplatin, etoposide, and atezolizumab, however, has not
TABLE 1 Patients with small cell component and who received first‐line chemoimmunotherapy
Note: Duration of follow‐up, PFS, and OS measured in months.
Abbreviations: carbo, carboplatin; etop, etoposide; atezo, atezolizumab; ICI, immune checkpoint inhibitor; LN, lymph nodes; OS, overall survival; PFS, progression free survival.
aUsed for adenocarcinoma of the prostate.
bFrom biopsy before differentiation to small cell histology.
TABLE 2 Other patients with neuroendocrine or small cell prostate cancer who received chemoimmunotherapy
cytokeratin 7 Negative: cytokeratin 20, PSA, PSAP,
NKX3.1 and P504S.
Note: Duration of follow‐up, PFS, and OS measured in months.
Abbreviations: carbo, carboplatin; etop, etoposide; atezo, atezolizumab; ICI, immune checkpoint inhibitor; LN, lymph nodes; OS, overall survival; PFS, progression free survival.
aWith the exception of patient #6, all prior systemic therapies were used for adenocarcinoma of the prostate. bUsed for relapsed small cell carcinoma of prostate. Previously had received carboplatin and etoposide alone in first line. cHeld atezolizumab during cycle 2 for nontoxicity reason. dFrom biopsy before differentiation to neuroendocrine histology. supported this hypothesis. To our knowledge, this is the first report of outcomes in a series of patients who were treated with frontline chemotherapy plus immunotherapy for prostate small cell/neu- roendocrine carcinoma.
Prostate cancer with small cell or neuroendocrine histology continues to be challenging to treat with systemic therapy. Past ef- forts to improve outcomes in small cell carcinoma of the prostate (like SCLC) have been largely unsuccessful. For example, a single‐arm, prospective trial adding doxorubicin to cisplatin and etoposide in small cell carcinoma of the prostate reported an unremarkable median PFS of 5.8 months. Since this anthracycline‐based combination added significant toxicity, further development of similar regi- mens was discouraged.7
On ther other hand, the biology of neuroendocrine prostate cancer suggested that ICIs may provide a new mechanism to improve outcomes. Molecular features such as high programmed death ligand 1 and tumor infiltrating lymphocytes more than 10% were observed in cases of prostate cancer with neuroendocrine differentiation.8 Although the predictive role of such findings is not established, they suggested that immunotherapy may have activity in this disease. In a Phase 2 trial of dual immunotherapy with ipilimumab and nivolumab in rare genitourinary malignancies, there were responses in 2 of 3 patients (67%) and 1 of 5 patients (20%) with small cell carcinoma of the bladder/upper tract and prostate, respectively.9 One case report described a patient who achieved a response to pembrolizumab for almost a year despite having platinum‐refractory disease.10
In the SCLC randomized trial, the median PFS in the atezolizu- mab + chemotherapy group was 5.2 months and patients received a median 7 cycles of ICI.5 To the contrary, for patients in our series who received first‐line chemoimmunotherapy, the median PFS was only 3.4 months and number of cycles of atezolizumab was 3.5. All patients had either progressive disease or died before 6 months after starting chemoimmunotherapy.
Putting these numbers in context is challenging given the rarity of prostatic small cell/neuroendocrine carcinoma. Prospective data are sparse and much of the existing literature lie in retrospective studies and case reports/series. Nonetheless, we can attempt to understand historical survival data by reviewing the largest samples: One analysis of the Surveillance, Epidemiology, and End Result reg- istry from 2004 to 2015 reviewed 260 patients with small cell carcinoma of the prostate; 1‐year survival was 42.1% and 68% of the patients presented with distant metastases. Median OS was 20, 11, and 8 months for local, regional, and metastatic disease, respec- tively.11 In one of the larger series, an MD Anderson review of 83 patients with SCC of the prostate from 1985 to 2005, median PFS
was 6 months with median disease‐specific survival of 13.1 months.12 While we acknowledge the inherent limitations of com- paring our experience with historical cohorts, the results of treating patients with SCC of the prostate with chemotherapy + atezolizumab do not appear to represent an improvement.
Our report is limited by a small sample size and the retrospective nature of this review. A large randomized trial would be necessary to look for small improvements in PFS or OS. One notable strength, however, is that by limiting our review to patients who received specific agents (carboplatin, etoposide, and atezolizumab), the confounding effect of heterogeneity in treatment regimens was minimized.
It is possible, however, that patients with other prostate cancer variants may benefit from this regimen. In our review, all patients had a histologic diagnosis of small cell or neuroendocrine carcinoma. On the other hand, Aparacio et al.13 reported that by including patients who had clinical characteristics (defined by seven criteria) suggestive of small cell‐ like biology, they were able to achieve a median OS of 16 months in a Phase 2 trial of first‐line carboplatin and docetaxel and second‐line cis- platin and etoposide. Adding immunotherapy to chemotherapy for patients with any clinical or genomic characteristics of an aggressive prostate cancer, regardless of histologic type, should be explored.

5 | CONCLUSIONS

Small cell or neuroendocrine carcinoma of the prostate was associated VP-16 with poor survival outcomes despite treatment with carbo- platin, etoposide, and atezolizumab. Including the present study, there has yet to be a demonstrated benefit of adding immunotherapy to chemotherapy in this setting.

CONFLICT OF INTERESTS
Dr. Pagliaro discloses research support from Exelixis, Merck, Pfizer, and Roche/Genentech. The other authors declare that there are no conflict of interests.

DATA AVAILABILITY STATEMENT
The data are not publicly available due to privacy or ethical restrictions.
ORCID
Christopher E. Wee https://orcid.org/0000-0003-0168-2069

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